Risks and risk monitoring in sotalol therapy for atrial fibrillation

Background: Atrial fibrillation (AF) stands as the most prevalent arrhythmia, significantly impacting both the prognosis and symptomatology of affected individuals. Healthcare expenditures associated with AF treatment and its related complications, in terms of morbidity and mortality, are substantial. In symptomatic AF, or in AF-induced left ventricular dysfunction, the primary treatment objective is to restore sinus rhythm. Earlier studies suggested equivalence between rate and rhythm control, but contemporary research points toward rhythm control being associated with lower rates of cardiovascular hospitalization and events. Cardioversion (CV) is often necessitated and is most effective when combined with an antiarrhythmic drug. Sotalol, a potent Ikr blocker, is one of the recommended drugs to prevent AF relapse. However, sotalol carries an inherent risk of proarrhythmias and sudden death. The proarrhythmic risk associated with sotalol in guideline-selected patients undergoing contemporary management remains unknown. Prolongation of the QT interval, measured on ECG, is considered the most reliable risk marker for ventricular arrhythmias in sotalol treatment. The dynamicity of the QT interval in patients receiving Ikr blocking drugs is poorly studied.

The thesis aimed to 1) evaluate the QT interval in patients after CV of AF with sotalol treatment and 2) compare mortality and the incidence of ventricular arrhythmias in patients following CV of AF who receive sotalol or beta-blockers.

Methods and results: Study I. Triplicate ECGs were recorded one hour after CV and one week later in 208 patients receiving a steady dose of sotalol or beta-blocker (metoprolol) treatment. In sotalol-treated patients, the mean QTc interval (QT corrected for heart rate) decreased during the week after CV (-20.3 ±24 ms), whereas no significant change was observed in metoprolol-treated patients (-2.5 ±18 ms). Longer QTc interval after CV and better renal function were associated with the reduction in QTc.

Study II. Twenty-four hour, 12-lead Holter recordings were conducted after CV in 50 patients treated with sotalol or metoprolol. Diurnal analysis of QTc revealed that 22% of sotalol-treated patients had >20% of all heartbeats with prolonged QTc >500 ms, primarily occurring during nighttime, compared to no patients treated with metoprolol. Diurnal variations were observed in both HR and QTc.

Study III. A nationwide register-based cohort study involving all Swedish AF patients included after their second CV from 2006 to 2017. Patients receiving sotalol (n=4,987) and cardioselective beta-blocker-treated patients (n=27,078), were followed for an average of 458 days. A diagnosis of heart failure was found in 14% of patients. All-cause mortality was lower in sotalol-treated patients, a difference that persisted in the propensity-matched comparison (n=4,953 in each group) with an incidence rate (IR) of 1.19 (0.93-1.49) vs. 2.01 (1.67-2.39) deaths per 100 patient years, and IRR of 0.59 (0.44-0.79). No differences were observed in ventricular arrhythmias with an IR of 1.38 (1.10-1.71) vs. 1.26 (1.00-1.57) events per 100 patient years, and an IRR of 1.59 (0.85-2.99).

Conclusions and summary: In AF patients after CV, selected for sotalol treatment after 2006, mortality or ventricular arrhythmias were not increased compared to patients treated with a cardioselective beta-blocker (Study III). The QTc interval significantly decreased during the week following CV to sinus rhythm in sotalol-treated patients (Study 1). Patients on sotalol exhibited a substantial number of heartbeats with prolonged QTc over 24 hours, particularly at night. QT dynamicity over 24 hours was evident in sotalol-treated patients, although the impact of the HR correction formula remains unclear (Study II). These findings could provide insight into the increased risk of proarrhythmias immediately after CV and indicate that the QT interval is a dynamic measure. Careful patient selection and the avoidance of congestive heart failure likely minimize the risks associated with sotalol treatment.

List of scientific papers

I. Lenhoff H, Darpö B, Ferber G, Rosenqvist M & Frick M. Reduction over time of QTc prolongation in patients with sotalol after cardioversion of atrial fibrillation. Heart Rhythm. 2016 Mar;13(3):661-8.
https://doi.org/10.1016/j.hrthm.2015.11.040

II. Lenhoff H, Darpö B, Page A, Couderc JP, Tornvall P & Frick M. Diurnal QT analysis in patients with sotalol after cardioversion of atrial fibrillation. Ann Noninvasive Electrocardiol. 2021 Jul 26(4):e12834.
https://doi.org/10.1111/anec.12834

III. Lenhoff H, Jarnbert-Petersson H, Darpo B, Tornvall P & Frick M. (2023). Mortality and ventricular arrhythmias in patients on d,lsotalol for rhythm control of atrial fibrillation - A nationwide cohort study. Heart Rhythm. 2023 Aug 18; S1547-5271(23)02589-4. https://doi.org/10.1016/j.hrthm.2023.08.019.
https://doi.org/10.1016/j.hrthm.2023.08.019